key: cord-0874769-snajbvr9 authors: Han, Zhiyong; Battaglia, Fortunato; Terlecky, Stanley R title: Discharged COVID‐19 Patients Testing Positive Again for SARS‐CoV‐2 RNA: A Minireview of Published Studies from China date: 2020-07-01 journal: J Med Virol DOI: 10.1002/jmv.26250 sha: 30396920ebb535bee1f35d28b1e75a2839e0425d doc_id: 874769 cord_uid: snajbvr9 In the ongoing COVID‐19 pandemic, one potential cause of concern is that some discharged COVID‐19 patients are testing positive again for SARS‐CoV‐2 RNA. To better understand what is happening and to provide public health policy planners and clinicians timely information, we have searched and reviewed published studies about discharged patients testing positive again for the SARS‐CoV‐2 RNA. Our search found 12 reports, all of which described patients in China. Our review of these reports indicates the presence of discharged patients who remain asymptomatic but test positive. However, it is unclear whether they are contagious because a positive RT‐PCR test does not necessarily indicate the presence of replicating and transmissible virus. Our review suggests the need for timely, parallel testing of different samples, including for example, fecal specimens, from COVID‐19 patients before and after they are discharged from hospitals. This article is protected by copyright. All rights reserved. COVID-19 results primarily from infection of the respiratory system by the SARS-CoV-2 virus, a member of the beta coronavirus family. Mechanistically, entry is afforded when the surface S (spike) protein of the virus binds to the transmembrane protein, angiotensin converting enzyme 2 (ACE2), in the plasma membrane of target cellswhich include nasal ciliated epithelial cells, nasal goblet/secretory cells, and type II alveolar pneumocytes. 1, 2 The infection initially causes pneumonia-like symptoms, such as cough, fatigue, and myalgia, 3-5 and later the viral tropism causes damage to the lungs, resulting in ground-glass-opacity (GGO) lesions that can be observed in chest CT or X-ray images. [3] [4] [5] The diagnosis of COVID-19 considers clinical symptoms, GGO lesions in chest CT or Xray images, and positive RT-PCR test results for the presence of SARS-CoV-2 RNA in patient samples. For the most part, it is the nasopharyngeal and oropharyngeal swabs that are tested. However, although the RT-PCR test is the most widely used method employed for the diagnosis of SARS-CoV-2 infection, a positive result only indicates presence of viral RNA but is not necessarily proof of the presence of infectious virus. 6 Most COVID-19 patients recover and are discharged from the hospital. [3] [4] [5] Nevertheless, a small but significant number of COVID-19 patients, especially those with underlying pre-existing conditions, such as hypertension, diabetes, and obesity, die due to This article is protected by copyright. All rights reserved. complications including acute respiratory distress, respiratory failure, multi-organ failure, and/or shock. [7] [8] [9] The mortality rate of COVID-19 is commonly calculated comparing the numbers of patients who were discharged alive versus those who died by the study end point. In a recent study by Richardson et al. employing such methods, of 2634 hospitalized COVID-19 patients in the New York City area, investigators calculated a 21% mortality rate. 10 For COVID-19 patients to be discharged from hospitals, they must meet strict criteria. For example, the guidelines of the National Health Commission of China state that patients must meet the following 4 benchmarks before they can be discharged: (i) be afebrile for at least 3 consecutive days, (ii) have significantly improved respiratory function, (iii) produce two negative SARS-CoV-2 RT-PCR test results at least 24 hours apart, and (iv) have significant improvement in lung GGO lesions determined by chest CT or X-ray imaging. 11 Note that the above discharge standards do not require patients to have complete resolution of lung GGO lesions, rather significant improvement in lung GGO lesions is acceptable when the other criteria are met. In China it is also required that discharged patients be quarantined for at least 14 days at specific post-discharge quarantine facilities or at home and are monitored for further improvement or any signs of relapse. 11 Given these strict discharge criteria, it was surprising to hear the announcement on February 25, 2020 that an estimated 14% of the discharged COVID- 19 We conducted searches in the PubMed database for reports that describe discharged examinations. Thus, our review focused on these 12 reports. During the search process, information was extracted by a single reviewer and then confirmed by others. The 12 reports we reviewed describe a total of 90 individuals who tested positive again in post-discharge follow-up examinations. 12-24 It should be emphasized that all of these patients had confirmed SARS-CoV-2 infection by RT-PCR testing, and most of them had GGO lesions in the lungs and had symptoms such as fever and cough on admission. Furthermore, prior to being discharged from hospitals, all of them met the 4 strict discharge criteria, including having at least 2 negative SARS-CoV-2 RT-PCR test results 24 hours apart . 11 Therefore, the post-discharge RT-PCR positivity was seen against the backdrop of these 2 negative RT-PCR results. The discharged patients were quarantined at designated quarantine centers, or in some cases in the same hospital where they had been treated, 18 or self-quarantined at home in accordance to the post-discharge rules in place. 11 They all received post-discharge follow-up examinations for signs of clinical symptoms and RT-PCR test for SARS-CoV-2 RNA. In Table 1 , we summarize the information about patients who tested positive for SARS-CoV-2 RNA in post-discharge, follow-up examinations in China as described in the 12 published reports. 12-24 As shown in Table 1 , we have included available patient information regarding symptoms and chest CT or X-ray image findings on admission, types of treatment received during hospitalization, and symptoms (or a lack thereof) at the time when the patient tested positive in the post-discharge follow-up examinations. These patients are in all age groups and are of both genders -most of them presented mild to moderate symptoms (fever and cough) on admission, and received treatments with several anti-viral drugs, such as oseltamivir, ritonavir, lopinavir, interferon, This article is protected by copyright. All rights reserved. and arbidol in hospitals (Table 1) . [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] Most of the individuals did not have symptoms or worsening of chest CT images when they re-tested positive (Table 1) . [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] In some of the studies, it was stated that patients who tested positive again for SARS-CoV-2 RNA but who were without clinical symptoms were nevertheless readmitted to hospitals for observation. None had symptomatic relapse during the rehospitalization (Table 1) . 14, 16, 18, 24 In the report by Peng et al, 18 it was noted that one patient developed nonorganic insomnia and another patient had increased anxiety during rehospitalization 18 ; in the report by Yuan et al, 20 it was noted that 8 patients had mild cough at the time of readmission. 20 We should point out that except in a few studies 12,13 it is not clear whether every discharged patient was subjected to RT-PCR test on consecutive days. Nevertheless, we note that in most studies they had tested throat swabsonly a few tested other samples, such as feces, nasopharyngeal swabs, and/or anal swabsfor patients before they were discharged. However, in the post-discharge follow-up examinations, sputum and anal swabs were the samples mostly tested ( Table 1) . None of the reports provide any reasons why different sampling approaches were employed before and after patient discharge. Most of the reports we reviewed are small case studies and therefore do not provide statistics regarding the percentage of patients who re-tested positive. However, two of the studies examined relatively large numbers of discharged patients. One followed 209 discharged patients and identified 22 patients (10.5%) who tested positive again at least once for SARS-CoV-2 RNA by RT-PCR. 19 The second study followed 172 patients and found 25 patients (14.5%) who similarly re-tested positive at least once. 20 It is somewhat surprising that the studies we found regarding discharged COVID- However, it is unlikely that this recommendation will be adopted because it involves an invasive procedure, which is not suitable solely for a diagnostic purpose. Our analysis indicates that many of the discharged patients tested positive for SARS-CoV-2 RNA when feces or anal swabs were employed, even though they tested negative at the same time when nasopharyngeal or oropharyngeal or sputum samples were examined. [15] [16] [17] [18] 20, 22 Future studies of larger numbers of patients are needed to determine whether or not some individuals still harbor (active) SARS-CoV-2 virus either in the respiratory system or the stool -or both -when they are tested in post-discharge examination protocols. It is also possible that the negative RT-PCR test results some patients received prior to their hospital discharge are false-negatives. 31 fibrobronchoscope brush biopsies were 46%; pharyngeal swabs were 32%; and feces were 29%. 26 Given that the viral RNA level in the sputum samples in the early and symptomprogressing phase was significantly higher than that in the recovery phase, 34, 35 and that there appears to be prolonged presence of SARS-CoV-2 RNA in the gastrointestinal tract of some infected individuals long after they had tested negative in their nasopharyngeal or oropharyngeal swabs, 26-30 it seems that depending on when, where, and how samples are taken from the body and processedthey may or may not contain sufficient amount of SARS-CoV-2 RNA to meet the detection sensitivity of the RT-PCR assays. Thus, it could be that the negative test results for some of the patients described in Table 1 were likely This article is protected by copyright. All rights reserved. due to a lack of sufficient SARS-CoV-2 virus in the tested throat swabs and nasopharyngeal swabs at the time when the viral load in the upper respiratory system might be low. 26 Therefore, it is important that respiratory and fecal samples from recovering COVID-19 patients are tested at the same time points before individuals are to be released from hospitals or examined in follow-up work. Finally, we should point out that one of the studies we reviewed describes 4 discharged health care workers who were self-quarantined at home. 15 It is stated that they took special care at home and that there was no evidence that they transmitted SARS-CoV-2 viruses to their family members, 15 Prior to retesting positive, he had not had SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Rehospitalization of a recovered coronavirus disease 19 (COVID-19) child with positive nucleic acid detection This article is protected by copyright. All rights reserved Positive RT-PCR Test Results in Patients Recovered From COVID-19 A case of a readmitted patient who recovered from COVID-19 in Chengdu Detection of SARS-CoV-2 by RT-PCR in anal from patients who have recovered from coronavirus disease 2019 Seven discharged patients turning positive again for SARS-CoV-2 on quantitative RT-PCR Positive RT-PCR tests among discharged COVID-19 patients in Shenzhen, China. Infect Control Hosp Epidemiol PCR assays turned positive in 25 discharged COVID-19 patients Positive result of Sars-Cov-2 in faeces and sputum from discharged patient with COVID-19 in Yiwu Prolonged presence of SARS-CoV-2 viral RNA in faecal samples Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding False-negative of RT-PCR and prolonged nucleic acid conversion in COVD-19: Rather than recurrence Sensitivity of chest CT for COVID-19: comparison to RT-PCR COVID-19 testing: the threat of falsenegative results Quantitative Detection and Viral Load Analysis of SARS-CoV-2 in Infected Patients SARS-CoV-2-Positive Sputum and Feces After Conversion of Pharyngeal Samples in Patients With COVID-19 We wish to thank Mr. Michael H. Oppenheim for his excellent editorial assistance. Prior to retesting positive, he had not had contact with any suspected or confirmed COVID-19 person.He was treated with a Chinese herbal medicine.